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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To explore the possibility that deregulated HOX gene expression might commonly occur during leukemic hematopoiesis, we compared the relative levels of expression of these and related genes in phenotypically and functionally defined subpopulations of AML blasts and normal hematopoietic cells. Initially, a semi-quantitative RT-PCR technique was used to amplify total cDNA from total leukemic blast cell populations from 20 AML patients and light density cells from four normal bone marrows. Expression of HOX genes (A9, A10, B3 and B4), MEIS1 and MLL was easily detected in the majority of AML samples with the exception of two samples from patients with AML subtype M3 (which expressed only MLL). Low levels of HOXA9 and A10 but not B3 or B4 were seen in normal marrow while MLL was easily detected. PBX1a was difficult to detect in any AML sample but was seen in three of four normal marrows. Cells from nine AML patients and five normal bone marrows were FACS-sorted into CD34+CD38-, CD34+CD38+ and CD34-subpopulations, analyzed for their functional properties in long-term culture (LTC) and colony assays, and for gene expression using RT-PCR. 93 +/- 14% of AML LTC-initiating cells, 92 +/- 14% AML colony-forming cells, and >99% of normal LTC-IC and CFC were CD34+. The relative level of expression of the four HOX genes in amplified cDNA from CD34- as compared to CD34+CD38- normal cells was reduced >10-fold. However, in AML samples this down-regulation in HOX expression in CD34- as compared to CD34+CD38- cells was not seen (P < 0.05 for comparison between AML and normal). A similar difference between normal and AML subpopulations was seen when the relative levels of expression of MEIS1, and to a lesser extent MLL, were compared in CD34+ and CD34- cells (P < 0.05). In contrast, while some evidence of down-regulation of PBX1a was found in comparing CD34- to CD34+ normal cells it was difficult to detect expression of this gene in any subpopulation from most AML samples. Thus, the down-regulation of HOX, MEIS1 and to some extent MLL which occurs with normal hematopoietic differentiation is not seen in AML cells with similar functional and phenotypic properties.
Leukemia 1999 May
PMID:Expression of HOX genes, HOX cofactors, and MLL in phenotypically and functionally defined subpopulations of leukemic and normal human hematopoietic cells. 1037 71

The use of immunodeficient mice, particularly of the nonobese diabetic/severe combined immunodeficient (NOD/SCID) strain, has allowed detection of very primitive malignant progenitors from patients with acute myelogenous leukemia (AML). To define the sensitivity and reproducibility with which the engraftment of different AML cells can be detected, 61 different samples from patients with newly diagnosed AML representing a variety of cytogenetic and French-American-British (FAB) subtypes were injected into NOD/SCID mice. Eight weeks after intravenous injection of 10(7) AML cells, the average percent of human cells in mouse bone marrow was 13.3%, with 70% of samples showing easily detectable engraftment of CD45(+) cells. AML samples with cytogenetic changes associated with a poor clinical prognosis tended to engraft to higher levels than those with changes associated with a good prognosis. Cells with FAB subtypes M3 and, to a lesser extent, M2, engrafted more poorly (P =.002 and.06, respectively) than those from other subtypes. Intraperitoneal injection of human interleukin-3 and Steel factor thrice weekly for 4 weeks did not enhance the levels of AML cell engraftment. However, AML samples that showed cytokine-independent colony growth in methylcellulose assay or expressed growth-factor mRNA in malignant blasts achieved significantly higher levels of engraftment than those which were cytokine dependent in culture or failed to express cytokine message (P <.03 and P <.02, respectively). In 6 patient samples, the frequency of NOD/SCID leukemia-initiating cells (NOD/SL-IC) varied from 0.7 to 45 per 10(7) cells, which was 200- to 800-fold lower than the frequency of AML long-term culture-initiating cells (AML LTC-IC) in the same samples. Each NOD/SL-IC will produce more than 10(6) leukemic blasts as well as many AML-CFC and AML LTC-IC as detected 8 weeks postinjection into mice. Serial transplant experiments showed the ability of NOD/SL-IC to maintain their own numbers over at least 3 to 4 weeks in vivo. The ability of these progenitors to self-renew combined with their potential to differentiate to produce large numbers of more mature progenitors and leukemic blasts suggests that the NOD/SL-IC assay identifies leukemic 'stem cells' that may maintain the malignant clone in human patients. The further use of this assay should facilitate studies of AML stem cell biology and the evolution of novel therapeutic strategies.
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PMID:Growth characteristics of acute myelogenous leukemia progenitors that initiate malignant hematopoiesis in nonobese diabetic/severe combined immunodeficient mice. 1047 2

The effect of expression of an O6-benzylguanine (O6-beG)-resistant mutant (hATPA/GA) of human O6-alkylguanine-DNA alkyltransferase (ATase) on the in vivo toxicity and clastogenicity of the anti-tumour agent N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU) to murine bone marrow has been investigated. When compared with control animals, the bipotent granulocyte-macrophage colony-forming (GM-CFC) progenitor population of the hATPA/GA transduced mice were somewhat more resistant to BCNU (1.4-fold, P = 0.047) and this effect was more significant in the presence of the ATase inactivator O6-beG (3. 5-fold, P = 0.001). The polychromatic erythrocytes were also significantly protected against BCNU-induced clastogenicity both in the presence (P < 0.001) and absence of O6-beG (P < 0.05). The primitive, multipotent spleen colony-forming cells (CFU-S) in these animals also showed moderate (1.6-fold, P = 0.034) protection in the absence of O6-beG but in the presence of the inactivator they remained as sensitive to BCNU toxicity as those in the control animals (P = 0.133). This result contrasts with previous findings demonstrating significant hATPA/GA-mediated, O6-beG-resistant protection against the toxicity and clastogenicity of a number of O6-alkylating agents, including temozolomide, fotemustine and chlorozotocin. The possibility that our strategy for protective gene therapy may be highly agent and cell-type specific is unexpected and has possible implications for clinical trials of this approach using BCNU or related agents.
Leukemia 1999 Nov
PMID:Protection of committed murine haemopoietic progenitors against BCNU toxicity does not predict protection of primitive, multipotent spleen colony-forming cells - implications for chemoprotective gene therapy. 1055 52

We have examined a possible role of two different types of irradiated stromal cells, i.e. murine bone marrow (BM) stromal cells and stromal cell line MS-5R, when cocultured with murine blood-borne progenitors or sorted Lin- Sca-1+ bone marrow cells in vivo in peritoneal diffusion chambers (DC). Retrieval and quantification of the cultured cells were performed after 4, 7, and 14 d. Granulocyte and/or macrophage colony-forming cells (G/M-CFC) were enumerated in subcultures from the DC. G/M-CFC production was not enhanced in the stroma-contact cultures, in comparison with the standard stroma-non-contact cultures, but early granulocytopoiesis was stimulated. Perturbation of the humoral environment of DC was investigated in a number of ways, for example with continuous infusion of rhG-CSF from a subcutaneous implanted minipump to DC host mice, with DC host mice carrying a transplantable leukaemia, secreting interleukin 3 (IL-3), and with injections of various cytokines. None of these interventions sustained the expansion of the G/M-CFC population. In conclusion, for ectopic haematopoiesis to take place, several requirements must be met. Relevant stromal cells apparently affect haematopoiesis both via direct cell-cell interactions and via humoral mediators (viz. cytokines) which they secrete.
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PMID:Ectopic haematopoiesis in the mouse: roles of stroma and cytokines in granulocytopoiesis in in vivo diffusion chamber cultures. 1058 May 63

One of the factors required for successful retroviral transduction is contact between viral particles and target cells. We hypothesized that combining agents that improve virus-target cell interaction via different mechanisms will increase transduction efficiency. We examined the transduction efficiency of leukemic K562 cells, primary normal and chronic myelogenous leukemia CD34+ cells with the amphotropic retroviral vector, G1Na, packaged in PA317 by enumerating G418-resistant colonies in semisolid media. We evaluated the ability of the recombinant fibronectin fragment, CH296, cationic lipids, or a transwell flow-through system, alone or in combination to improve retroviral transduction. Transduction of K562 cells improved 1.5 to two-fold with lipids or CH296, while their combination improved transduction 2.5-fold. Transduction of K562 cells in the transwell flow-through system improved transduction three-fold. Transduction of normal (NL) CD34+ CFC improved 10-fold with lipids and 20-fold with CH296. Lipid and CH296 had synergistic effects. The transwell flow-through system improved transduction of normal CD34+ CFC 30-fold. Finally, similar to what was seen for K562 cells, transduction of CML CFC improved two- to three-fold with either CH296 or lipids, whereas the combination had synergistic effects. We conclude that any physical means that enhances contact between viral particles and target cells improves transduction. Two such methods that have different action mechanisms have additive or synergistic effects on transduction.
Leukemia 2000 Feb
PMID:Improved retroviral transduction of hematopoietic progenitors by combining methods to enhance virus-cell interaction. 1067 49

Angiotensin I-converting enzyme (ACE) has been shown to be involved in the catabolism of the tetrapeptide acetyl-Ser-Asp-Lys-Pro (AcSDKP). As AcSDKP is a physiological inhibitor of haematopoietic stem cell proliferation, we investigated the in vitro and in vivo effects of captopril, one of the specific inhibitors of ACE, on the proliferation of primitive haematopoietic cells. Regenerating bone marrow cells obtained from mice given one injection of cytosine arabinoside (100 mg/kg) as well as SA2 myeloid leukaemia cells were incubated in vitro for 24 h with 10-6 M captopril. Captopril significantly reduced the proportion of high proliferative potential colony-forming cells (HPP-CFC-1) in S-phase, whereas it had no effect on the proportion of SA2 leukaemic colony-forming cells in S-phase. When given in vivo to mice 1 h after 2 Gy gamma-irradiation or cytosine arabinoside (AraC) injection, captopril (100 mg/kg) was shown to prevent HPP-CFC-1 entry into S-phase induced by these cytotoxic treatments. The observed effects correlated with a reduction in ACE degradative activity and an increase in the level of endogenous AcSDKP both in the supernatants of captopril-treated bone marrow cells and in plasma of treated animals. The present findings suggest that AcSDKP might mediate the observed in vitro and in vivo inhibitory effects of captopril on primitive haematopoietic cell proliferation.
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PMID:Captopril inhibits in vitro and in vivo the proliferation of primitive haematopoietic cells induced into cell cycle by cytotoxic drug administration or irradiation but has no effect on myeloid leukaemia cell proliferation. 1088 5

Human haemopoietic stem and progenitor cells may be distinguished by the pattern of cell surface markers they display. The cells defined as 'stem' cells are heterogeneous and lack specific markers for their detection. However, they may be identified in in vitro assays such as the long-term culture initiating cell (LTC-IC) and in transplant assays involving immunosuppressed NOD/SCID mice. It is still not clear to what extent, if any, these cell populations overlap. The chemokine macrophage inflammatory protein-1alpha (MIP-1alpha) prolongs survival of LTC-IC in suspension cultures and we now show that in longterm bone marrow cultures (LTBMC) maintenance of haemopoiesis was significantly better from the CD34+ cells which possess MIP-1alpha receptors (P < 0.006). We examined one MIP-1alpha receptor, CCR1, which is present on CD34+ cells from haemopoietic tissues. In LTBMC the production of GM-CFC from CD34+CCR1- cells was significantly higher (P < 0.02) than that from CD34+CCR1+ cultures and the incidence of LTC-IC was 3- to 6-fold higher in the CD34+CCR1- cell fraction. In contrast, the cells responsible for high levels of engraftment in NOD/SCID mice were contained in the CD34+CCR1+ cell fraction. The CD34+CCR1+ cells engrafted to high levels in NOD/SCID and generated large numbers of progenitor cells. Therefore, we conclude that LTC-IC and SRC may be distinguished on the basis of expression of the chemokine receptor CCR1.
Leukemia 2001 Jul
PMID:NOD/SCID repopulating cells but not LTC-IC are enriched in human CD34+ cells expressing the CCR1 chemokine receptor. 1145 79

The first definitive long-term repopulating hematopoietic stem cells (HSCs) emerge from and undergo rapid expansion in the embryonic aorta-gonad-mesonephros (AGM) region. To investigate the presumptive unique characteristics of the embryonic hematopoietic microenvironment and its surrounding tissues, we have generated stromal clones from subdissected day 10 and day 11 AGMs, embryonic livers (ELs) and gut mesentery. We here examine the ability of 19 of these clones to sustain extended long-term cultures (LTCs) of human CD34(+) umbilical cord blood (UCB) cells in vitro. The presence of in vitro repopulating cells was assessed by sustained production of progenitor cells (extended LTC-CFC) and cobblestone area-forming cells (CAFC). The embryonic stromal clones differed greatly in their support for human HSCs. Out of eight clones tested in the absence of exogenous cytokines, only one (EL-derived) clone was able to provide maintenance of HSCs. Addition of either Tpo or Flt3-L + Tpo improved the long-term support of about 50% of the tested clones. Cultures on four out of 19 clones, ie the EL-derived clone mentioned, two urogenital-ridge (UG)-derived clones and one gastrointestinal (GI)-derived clone, allowed a continuous expansion of primitive CAFC and CFU-GM with over several hundred-fold more CAFC(week6) produced in the 12th week of culture. This expansion was considerably higher than that found with the FBMD-1 cell line, which is appreciated by many investigators for its support of human HSCs, under comparable conditions. This stromal cell panel derived from the embryonic regions may be a powerful tool in dissecting the factors mediating stromal support for maintenance and expansion of HSCs.
Leukemia 2002 Sep
PMID:Stromal cells from murine embryonic aorta-gonad-mesonephros region, liver and gut mesentery expand human umbilical cord blood-derived CAFC(week6) in extended long-term cultures. 1220 Jun 94

Expansion of primitive hematopoietic progenitor cells (HPC) is a major challenge in stem cell biology. Stimulation by growth factors (GF) is essential for proliferation of HPC, while the role of stromal cell coculture for maintenance of progenitor/stem cell potential is unclear. We evaluated the potential of a murine stromal cell layer providing hematopoietic GF to support expansion of human CD34(+) cells. Murine MS-5 cells were transfected with the cDNA encoding huFlt3 ligand and the interleukin6/sinterleukin-6R fusion protein hyper-IL-6. Expansion of CFC and week6 CAFC was at least as efficient in transfected clones compared to control cocultures supported with exogenous GF. Cell numbers reached 17.5- to 62.3- (day 14) and 17.4- to 92.4-fold (day 21) of input cells. Expansion of CFU-GM/Mix was 4.0- to 12.8-fold (day 14) and 4.9- to 11.7-fold (day 21). Primitive week6 CAFC were expanded up to 6.5-fold (day 14) and 6.2-fold (day 21) without exogenous GF. When direct contact of HPC and stromal cells was inhibited, a loss of CFC and much more of CAFC potential was observed with unaffected overall cell proliferation. Here, we show the generation of GF producing murine stromal cells which efficiently support early hematopoiesis without exogenous GF. Direct stromal cell-HPC contact is advantageous for maintenance of differentiation potential.
Leukemia 2002 Oct
PMID:Murine stromal cells producing hyper-interleukin-6 and Flt3 ligand support expansion of early human hematopoietic progenitor cells without need of exogenous growth factors. 1235 66

Nectins are recently described adhesion molecules that are widely expressed on many tissues, including the hematopoietic tissue. Nectin 1 (CD111) is expressed on a higher proportion of mobilized peripheral blood (mPB) than cord blood (CB) CD34+ cells, and of CD34+/CD38+ cells when compared with CD34+/CD38- cells. We studied functional properties of human CB and mPB CD34+ cells that express low or high levels of CD111. CD34+/CD111(dim) cells contain a higher proportion of cells in G0/G1 phase than CD34+/CD111(bright) cells. CD34+/CD111(bright) cells contain more erythroid progenitors: CFU-E, than their counterparts, which on the opposite contain more HPP-CFC. Limiting dilution analyses demonstrate a higher frequency of immature progenitors: cobblestone-area colony-forming cells, CD34+/CD111(dim) than in CD34+/CD111(bright) cells. In vitro differentiation assays demonstrate a higher frequency of B-, T- and dendritic-cell precursors, but less NK-cell precursors in CD34+/CD111(dim) cells. Evaluation of engraftment in NOD-SCID mice shows that SCID repopulating cells are more frequent among mPB CD34+/CD111(dim) cells. Liquid culture of CD34+/CD111(dim) cells with erythropoietin shows that CD111 expression increases simultaneously with CD36, following CD71 and before glycophorin A expression. In conclusion, immature human hematopoietic progenitors express low levels of CD111 on their surface. During erythroid differentiation CD34+ cells acquire higher levels of the CD111 antigen.
Leukemia 2003 Jun
PMID:Functional characterization of human CD34+ cells that express low or high levels of the membrane antigen CD111 (nectin 1). 1276 81


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